Genetics of t(14;18)-negative follicular lymphoma. Follicular lymphoma t(14;18)-negative

The pathogenesis of t(14;18)-negative follicular lymphoma (FL) remains largely unknown. Therefore, 55 cases of t(14;18)-negative, mostly BCL2 protein negative FL, were genetically characterized by targeted sequencing and copy number (CN) arrays. t(14;18)-negative FL predominated in women (M:F 1:2), patients often presented with early clinical stages (68%) and had excellent prognosis. Overall, t(14;18)-negative FL displayed CN alterations (CNA) carried by conventional t(14;18)-positive FL (cFL) but with different frequencies. The most frequently mutated gene was STAT6 (57%) followed by CREBBP (49%), TNFRSF14 (39%) and KMT2D (27%). We identified two robust molecular clusters with some clinico-pathological correlations. Cluster A was characterized by TNFRSF14 mutations/1p36 alterations (24/25, 96%), and frequent mutations in epigenetic regulators with recurrent loss of 6q21-24 resembling cFL. Cluster B showed few genetic alterations; however, a subgroup with STAT6 mutations concurrent with CREBBP mutations/16p alterations without TNFRSF14 and EZH2 mutations was noted (13/20, 65%). These two molecular clusters were unable to separate cases in terms of inguinal localization, growth pattern or presence of STAT6 mutations. BCL6 rearrangements were demonstrated in 10/45 (22%) cases and did not cluster together. Cases with inguinal presentation (30/55; 55%) had higher frequency of diffuse growth pattern, STAT6 mutations and CD23 expression (P<.05), and lower number of CNA in comparison with non-inguinal cases (5.3 vs 9.1/alterations per case) (P=.02). STAT6 mutations have a positive correlation with CD23 expression in t(14;18)-negative FL (P<.001). In conclusion, t(14;18)-negative FL is clinically and genetically a heterogeneous disorder with genetic features that differ from cFL, nodal marginal zone lymphoma and pediatric-type FL.